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Clinical Data Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS with multi-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated the safety and efficacy of defibrotide in adult and pediatric patients with established hepatic VOD/SOS and advanced MOF. Patients (n=102) given 25 mg/kg/day defibrotide were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by a blinded independent medical review committee. Baseline characteristics between groups were well balanced. The primary objective was to compare survival at Day+100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25.0% in the control group (estimated difference of 23.0%; 95.1% confidence interval [CI] 5.2%-40.8%; P=.0109, using a propensity-adjusted analysis based on 4 prognostic factors of survival). Observed Day+100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% in the controls (19.0% difference using similar methodology; 95.1% CI 3.5-34.6; P=.0160). Defibrotide was generally well-tolerated with manageable toxicity. Related adverse events included hemorrhage or hypotension; there was no difference in the incidence of common hemorrhagic adverse events (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal [7.8% and 9.4%]) between the defibrotide and control groups, respectively. Defibrotide was associated with significant improvement in Day+100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality.

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